Project Summary This project addresses fundamental mechanisms that may contribute to the acute symptoms of concussion and related mild traumatic brain injuries. Our long-term goal is to increase understanding of mechanisms underlying acute neurological dysfunction, so that diagnosis and/or treatment can be substantially improved. This work is expected to be significant for the large number of individuals who suffer from concussions, including the substantial number who do not recover fully after single or repetitive hits. The project focuses on the phenomenon of Spreading Depolarization (SD), which has emerged relatively recently as a key contributor to lesion progression in patients in the ICU with severe traumatic brain injury or stroke. There is very limited knowledge about whether SDs occur in other neurological conditions. In 2018 we presented the first evidence that SDs occur in a murine concussion model, and another group provided a first publication with indirect measurements of SD in a similar model. The challenge now is to provide additional direct electrophysiological recordings of SD, combined with simulatenous measures of behavior, to determine whether concussion-induced SDs are responsible for the well-known acute symptoms of concussion. If SDs are necessary and sufficient to explain the symptoms, then interventions targeting SD could be very valuable for these patients, and the discovery could suggest new opportunities for early diagnosis. Furthermore, the large disruptions in neuronal and vascular function caused by SD could contribute to a window of vulnerability to second hits ? a possibility that has not previously been investigated. This project therefore addresses key gaps in knowledge about mechanisms linking SD to concussion symptoms and vulnerability. We will use a mouse concussion model and combinations of electrophysiological and behavioral recordings, together with high-throughput anatomical analyses to assess for signs of neuronal injury. Specific Aim 1 tests whether the short term depression of synaptic activity that follows SD underlies post-concussion behaviors. Specific Aim 2 tests whether the massive disruptions in blood flow and/or synaptic activity that follow SD render the brain more vulnerable to a second hit during this acute phase. Successful completion of these aims is expected to identify SD as a significant contributor to the symptoms and consequences of concussion, and open new doors to detection and treatment of this very common and often severely debilitating type of brain injury. The project is very well suited to the interdisciplinary environment of the COBRE Center. Extensive input from both preclinical and clinical mentors and colleagues, and excellent core facilities will provide an outstanding platform for multiple high-impact publications and progression to independent extramural funding success.